by Dr. C.D. Buckner M.D. Medically reviewed by C.H.Weaver M.D. 10/2021
High-dose chemotherapy and allogeneic bone marrow or blood stem cell transplantation is a treatment strategy that utilizes the administration of high doses of anti-cancer drugs and/or radiation therapy for the purpose of killing cancer cells and transplantation of stem cells to “rescue” or restore bone marrow blood and immune cell production. Transplantation is the term for transfer of tissue (a graft) from one person to another. Allogeneic is the term for a tissue graft from one person to another.
There are many types of allogeneic grafts that can be transplanted from one person to another, including skin, heart, kidney, liver, etc. However, the easiest organ in the body to transplant is the bone marrow. This is because a small quantity of stem cells taken from the bone marrow or peripheral blood of one person can repopulate the entire bone marrow organ of another person. In contrast to other types of transplants, the donor does not “miss” the small amount of bone marrow stem cells removed. A small quantity of bone marrow contains stem cells that are capable of dividing rapidly and repopulating the entire blood and immune system of another person within a short period of time.1-4
High-dose chemotherapy and allogeneic stem cell transplantation is a component of an overall treatment strategy utilized to treat many kinds of cancers and blood disease. Allogeneic stem cell transplant has through various refinements continues to become more effective and safe. A recent analyses of patients treated at Fred Hutchinson Cancer Center showed that patients treated between 2013 and 2017 had improved survival and were less likely to suffer significant side effects that those undergoing transplant 10 years previously.4
Allogeneic stem cell transplantation may be appropriately utilized as the initial or subsequent treatment depending on the type of cancer. It is not a treatment of last resort. The timing of stem cell transplantation in the management of a specific cancer should be carefully planned following an initial diagnosis of cancer.
Cancers Treated with alloSCT
High-dose chemotherapy and allogeneic stem cell transplantation is the best treatment for certain cancers because it improves survival and cures more patients than other treatments. High-dose chemotherapy is currently being evaluated in controlled clinical trials for the treatment of other cancers. The results achievable with high-dose chemotherapy for the treatment of specific cancers have been published and best describe the role of stem cell transplantation for the following cancers:
- Acute Myeloid Leukemia
- Acute Lymphoblastic Leukemia
- Chronic Lymphocytic Leukemia
- Chronic Myeloid Leukemia
- Multiple Myeloma
- Hodgkin Lymphoma
- Myelodysplastic Syndrome MDS
- Non Hodgkin Lymphoma
Learn more about allogeneic stem cell transplantation and the role it may play in the treatment of your cancer...
- Selecting a Transplant Program
- Donor Selection
- Stem Cell Collection
- Side Effects of Transplant
Stem Cell Center & Program Selection
A stem cell center consists of designated inpatient and outpatient treatment facilities with doctors and nurses experienced in stem cell transplantation. Three decades of continuous technological improvement have allowed high-dose chemotherapy and stem cell transplantation to become safe and widely available. There are currently over 200 centers that provide high-dose chemotherapy and stem cell transplantation services in the United States, including large cancer centers, community hospitals and physician practices. The increased availability of stem cell transplants to patients has allowed many patients to benefit from this treatment approach who otherwise could not have traveled away from their family and support system. Its important to select a program with expertise in treating your cancer and a proven track record of performing the procedure. When choosing a stem cell center, the following objective criteria may be useful in selecting a center:
Center Volume: The American Society of Blood and Marrow Transplant (ASBMT) recommends that a center perform at least 10 transplants in the previous year to maintain proficiency.
Quality of Staff: The ASBMT recommends that each center have a transplant team that includes a “program director” and at least one other physician experienced in transplant medicine. The director should be board certified and have 2 years experience or 1 year training in transplant medicine. You may also want to know which physician will actually provide your care. Will it be the program director, other physicians, or fellows (doctors in training)? The continuity of nursing care is also important, since the majority of care is actually delivered by the nurses. A single coordinating nurse can be invaluable. You may want to ask which nurses will be involved with your care and how frequently they will change.
Continuity of Care: Will a single or multiple doctors oversee your care during and after the high-dose chemotherapy treatment? If you are leaving your primary doctor to receive your care at a transplant center, it is important to know whether you can receive all your care and follow up at the transplant center. If not, then how well does that center communicate with your primary doctor concerning your long-term treatment plan and management of potential complications. Many patients prefer to receive their treatment close to home with a single doctor to ensure good continuity of care.
Outcomes: Evaluating the actual treatment results may be the most useful criteria when selecting where to receive treatment. The ASBMT recommends that each center keep accurate patient records that include specific treatment outcome information. Asking the following questions may help you choose one center over another.
- What are the cure and survival rates for patients treated in the center with your specific cancer?
- What is the average duration of hospital stay?
- What are the mortality rates reported by the center?
Patient Satisfaction: Ask to talk with a patient who has been treated in the center, as well as to see the results of patient satisfaction surveys. All good centers can arrange for a new patient to talk to other patients that have been previously treated at the center.
Facility Infrastructure: The ASBMT recommends that facilities where high-dose chemotherapy is delivered have designated inpatient and outpatient areas, standard policies regarding infection control and the ability to evaluate patients on a 24-hour basis. Programs should also have a stem cell processing capability and 24-hour blood bank support. Accreditation of stem cell processing facilities began in 1997 and is currently being performed by the American Association of Blood Banks (AABB) and the Foundation for Accreditation of Hematopoietic Cell Therapy (FAHCT).
Allogeneic vs. Autologous: Lastly, the type of transplant being performed may also dictate where you choose to receive treatment. In general, an unrelated donor transplant requires more infrastructure and experience to perform than a matched sibling allogeneic transplant or an autologous transplant. Some of the largest centers performing unrelated donor transplants produce the best outcomes for patients. On the other hand, many small autologous transplant centers produce equal or better outcomes than large centers. Take the time to evaluate all potential centers and choose the center, physician, staff and environment where you feel most comfortable receiving your treatment.
Allogeneic stem cell transplant is the best, and occasionally the only, curative treatment option for certain cancers. For these patients, a timely search for the best available stem cell donor can be life-saving.
The goal of selecting a stem cell donor is to provide the best “match” between the donor and the patient (host). The body’s immune defense system consists of white blood cells that travel continuously throughout the body in surveillance of foreign substances or cells. They destroy what they perceive as “non-self”. When donor stem cells are transplanted into a new host, several donor-host interactions may occur. On one end of the spectrum, the host’s immune system may reject the donor’s cells (i.e., graft rejection or failure). On the other end, the donor’s cells may attack (reject) the recipient’s tissues in what is called graft-versus-host reaction.
Cells have surface antigens that can recognize and reject foreign tissues. These are called human leukocyte antigens or HLAs. Donors are selected on the basis of blood testing (tissue typing) for HLA antigens. The major HLA antigens determine tissue compatibility and are located on the 6th chromosome. Four sets of HLA antigens have so far been identified: A, B, C, D. To ensure the best possible acceptance of donor stem cells, it is best to match all of the four HLA antigen sites.
- HLA-Matched Family Members
- Haploidentical Donors
- Unrelated Donors
- Umbilical Cord Blood
HLA Matched Family Members
Originally, donor and recipient were exclusively siblings who had inherited the identical 6th chromosomes from the father and mother. In this situation, all of the HLA antigens (and all other antigens) located on the 6th chromosome are identical between donor and recipient. However, in some instances a parent can be matched with a child or a child with a parent. In addition, if the mother and father have similar HLA antigens siblings can be a suitable matches without inheriting the same 6th chromosome. It is therefore important to test blood samples from the entire immediate family ,i.e., parents, siblings and children.
A transplant using stem cells from a donor whose HLA type is a half-match for the recipient is referred to as haploidentical. This alternative procedure called a haploidentical stem cell transplant is designed to provide the benefits of stem cell transplant with a lower risk of GVHD. In a haploidentical transplant, doctors transplant cells that aren’t an identical match. These “half matched” cells can come from family members. Parents and children are always a half match for each other, and siblings have a 50% chance of being a half match for each other. In addition to lowering the risk of GVHD compared with an unrelated allogeneic transplant, haploidentical transplants also helps doctors find potential donors more quickly.
Haploidentical stem cell transplants are increasingly used for individuals who have been unable to find a more closely matched donor. A recently published clinical trial in patients with acute myeloid leukemia (AML) has demonstrated that a haploidentical related donor stem cell transplant has resulted in similar survival as a transplant from an unrelated matched donor. Furthermore, transplant from a half matched donor appeared to lower the risk of graft-versus-host disease (GVHD).
To compare outcomes between haploidentical and allogeneic transplants, researchers studied both techniques in 192 patients with AML who underwent haploidentical transplant and 1,982 patients who underwent allogeneic transplant from a closely matched unrelated donor. Patients who received haploidentical transplants had a lower incidence of GVHD compared with the allogeneic treatment group with both myelablation and reduced intensity conditioning regimens. Survival outcomes between haploidentical and allogeneic transplants were mixed but fairly similar. On the one hand, patients in the haploidentical group who received myeloablative treatment had a slightly lower probability of three-year survival compared with allogeneic patients (45% versus 50%, respectively). On the other hand, patients in the haploidentical group with reduced intensity conditioning transplants had a slightly higher probable three-year survival at 46% versus 44%. This research may help patients for whom finding a matched unrelated donor is difficult as well as provide an option for stem cell transplant with lower risk of GVHD.
More recently, there has been considerable success in using unrelated individuals as bone marrow or blood stem cell donors. An unrelated donor is obtained by a computerized search carried out by the National Marrow Donor Program (NMDP), which is sponsored by the National Institutes of Health. This search is initiated by the transplant center that will provide your treatment. You can get an immediate estimate of the probability of finding a donor for a given patient by using the “World Book,” which is a registry of all of the potential donors in the NMDP plus all of the other international unrelated donor banks. Your HLA type is submitted to this service by your transplant center at no cost and the number and location of potential donors is immediately available.5
This is helpful at the outset, as it provides you with important information about the likelihood of finding a donor and how long it will take.Once potential donors are identified by the NMDP, detailed blood testing has to be performed to confirm compatibility between donor and recipient. This requires obtaining blood samples from the patient and the prospective donor. Some donors will turn out not to be compatible on more extensive testing and some donors may be more compatible than others. This extensive testing makes identification of a donor a much longer procedure than that necessary to identify a family member donor.
The National Marrow Donor Program was established in the mid-1980’s and had less than 250,000 donors in 1990. Now with more than 5 million donors listed in the registry and thousands of transplants performed using unrelated donors provided by the NMDP. With the current number of donors in the registry, more than 70% of patients are able to find a suitable match. Donor identification is significantly lower for patients in racial minorities.
One limitation of the NMDP is the time it takes to locate a donor. The median time from initiation of a search to donor identification is now approximately 10 weeks, which is an improvement from the 6-month searches of the past. Therefore, it is important to initiate a search early in the disease course, especially for diseases that are rapidly progressive, such as the acute leukemias. Donors can be found more rapidly for patients with common HLA types than for patients with less common HLA types. Sometimes it is helpful to do a quick survey of donor availability by performing a “World Book” search as mentioned above.
Umbilical Cord Blood
Human umbilical cord blood (UCB) is a rich source of the stem and progenitor cells that are present in bone marrow. Cord blood from related and unrelated donors has been successfully transplanted in children and adults worldwide. Due to the relatively small number of cells infused per kilogram of body weight in adults however cord blood may need to be “expanded” in culture for adult transplants. In general, cord blood is utilized when no suitable family member or unrelated donor is available.
Parents can also have the cord blood cryopreserved at the time of delivery of a child. This has been useful when a prior child has a disease treatable by marrow or blood stem cell transplantation and there is no other donor available.Umbilical cord blood is cryopreserved in “cord blood banks”. HLA typing is performed and available for computer matching in the same way that the NMDP performs unrelated donor searches. Approved transplant centers are provided with the frozen cells when needed.
Stem Cell Collection
Following the delivery of high-dose therapy to patients for the treatment of cancer, infusion of stem cells is necessary to ensure recovery of bone marrow function and production of red blood cells, white blood cells and platelets. Historically, stem cells were harvested from bone marrow, but more recently, many cancer centers have adopted the practice of collecting stem cells from peripheral blood
Techniques of Stem Cell Collection Harvesting
The collection of stem cells from bone marrow has been safely performed for over 30 years. A bone marrow harvest is relatively simple and typically occurs in the operating room. During a bone marrow harvest, patients receive general anesthesia and then a surgeon inserts a large needle directly into the bone marrow cavity of bones of the lower back after the area has been sterilized. Bone marrow is aspirated or sucked out of the bones by inserting the needle into the bone multiple times. A typical bone marrow harvest takes about two hours and involves the removal of one liter of bone marrow containing the stem cells. The major side effect of this procedure is discomfort at the site of the bone marrow harvest. Infrequent complications include bleeding, infection and nerve damage.
Peripheral Blood Stem Cell Harvesting
The collection of stem cells from the blood is slightly more complicated than collection from bone marrow and has been performed safely for over a decade. Collecting stem cells from the peripheral blood may also have several clinical advantages compared to collecting them from bone marrow.
Stem cells normally circulate in the blood in very small quantities and can be collected from the blood through a small catheter inserted into a patient’s vein. The number of circulating stem cells in the blood is increased in patients whose bone marrow is recovering from chemotherapy. Cytokines (blood cell growth factors) administered to patients after myelosuppressive chemotherapy can also cause a 100-fold increase in the number of stem cells circulating in the blood. Injection of cytokines stimulates increased production of immature and mature bone marrow stem cells and their release into the blood where they can be collected. Cytokines can also be administered without chemotherapy and cause a substantial increase in the number of circulating blood stem cells for collection. The process of delivering a cytokine or growth factor with or without myelosuppressive chemotherapy for the purpose of collecting stem cells is referred to as “stem cell mobilization”. Two cytokines, Neupogen® and Leukine™, stimulate the bone marrow’s production of stem cells and are approved by the Food and Drug Administration for use in patients to increase the number of circulating stem cells and several others are in development.
During stem cell mobilization, patients receive an injection of a cytokine and are evaluated daily. The process of actually collecting the stem cells from the blood is called apheresis and this begins when there are sufficient stem cells circulating in the blood for collection. Stem cells are collected with an apheresis machine from the blood flowing through a catheter inserted into a vein. Blood flows from a vein through the catheter into the apheresis machine, which separates the stem cells from the rest of the blood and then returns the blood to the patient’s body. Apheresis is performed for several days until enough stem cells have been collected to support treatment with high-dose chemotherapy. Most donors have sufficient stem cells collected with 2-4 days of apheresis
Stem cells can be reliably identified and accurately measured because they have a specific marker or label on the stem cell surface. This marker is referred to as the CD34 antigen. Measuring the number of CD34 antigen-positive stem cells is important because doctors can accurately predict how fast the bone marrow recovers after high-dose chemotherapy administration based on the number of CD34 positive stem cells infused. Daily measurement of the CD34+ peripheral blood stem cell content is also useful for determining the number of days to perform apheresis.
An optimal number of stem cells to support rapid bone marrow recovery and blood cell production after treatment with high-dose chemotherapy is approximately 5 million CD34+ cells/kg patient weight. Infusion of over 5 million cells/kg results in the majority of patients recovering bone marrow blood cell production in only 10-21 days. The minimal number of allogeneic stem cells necessary to ensure safe recovery of bone marrow blood cell production is currently unknown.
Bone Marrow or Peripheral Blood Stem Cells
Stem cells collected from blood are associated with more rapid bone marrow recovery and greater ease of collection than stem cells collected from bone marrow. Comparisons evaluating stem cells collected from bone marrow and stem cells collected from peripheral blood have been performed in patients undergoing allogeneic stem cell transplant. Patients infused with stem cells collected from blood have faster recovery of bone marrow blood cell production; fewer red blood cell and platelet transfusions; and shorter admissions to the hospital than patients treated with allogeneic stem cells collected from bone marrow.
Aromatase Inhibitor joint pain can be managed with anti-inflammatory medications, exercise and Duloxetine.
Depression Drug Reduces Joint Pain for Women with Early Stage Breast Cancer
Physicians at The Fred Hutchinson Cancer Center, City of Hope and Stanford University performed a randomized clinical trial comparing allogeneic bone marrow transplantation to peripheral blood stem cell transplantation in patients with leukemia and lymphoma. The results of this study were presented at the American Society of Hematology Annual Meeting. The study had a planned accrual of 200 patients, but was terminated after entry of only 138 patients because of improved survival in the patients with advanced leukemia and lymphoma receiving peripheral blood stem cells compared to bone marrow transplants.
Patients receiving peripheral blood stem cells experienced more rapid recovery from treatment than patients receiving bone marrow transplants. White blood cell counts recovered 5 days earlier and platelets recovered 8 days earlier. There was no difference in the incidence of acute graft-versus-host disease and there was an increase in the incidence of chronic graft-versus-host disease of approximately 10% in patients receiving peripheral blood stem cells.
The physicians concluded that allogeneic peripheral blood stem cells were superior to bone marrow stem cells however transplant centers continue to evaluate both in the hope of making transplant more effective.
Side Effects of Allogenic Stem Cell Transplant
Historically side effects of allogeneic stem cell transplant have limited the availability of the therapy to younger patients and those with ideal donors. Improvements in supportive care, donor selection and the use of reduced intensity treatment regimens have significantly improved the safety of transplant and expanded its use allowing more patients to benefit from this therapy.
In general the type and severity of the side effects that occur with allogeneic stem cell transplant are influenced by the degree of HLA matching between donor and recipient; the condition and age of the patient; the specific high-dose chemotherapy treatment regimen; and the degree of suppression of the immune system. The more common side effects are well described and carefully monitored for by the transplant team.
Graft-versus-Host Disease (GVHD)
Graft-versus-host disease is a common complication of allogeneic stem cell transplant. Lymphocytes contained in donated stem cells cause a reaction called graft-versus-host disease. In this reaction, lymphocytes from the donor attack cells in the body of the recipient especially in the skin, gastrointestinal tract and liver. The common symptoms of acute graft-versus-host disease are skin rashes, jaundice, liver disease and diarrhea. Graft-versus-host disease also increases a patient’s susceptibility to infection. Graft-versus-host disease can develop within days or as long as 3 years after transplantation. Generally, graft-versus-host disease that develops within 3 months following transplantation is called acute graft-versus-host disease, whereas graft-versus-host disease that develops later is called chronic graft-versus-host disease.
There are several different drugs administered after allogeneic stem cell infusion to prevent or ameliorate graft-versus-host disease. Doctors don’t want to completely eliminate GVHD because it also has an anti-cancer effect. Donor lymphocytes also kill cancer cells and doctors refer to this as a graft-versus-cancer effect. Doctors try to maintain a delicate balance between optimizing the graft verses cancer effect while minimizing GVHD.
Bone Marrow Suppression
High-dose chemotherapy directly destroys the bone marrow’s ability to produce white blood cells, red blood cells and platelets. Patients experience side effects from neutropenia or low numbers of white blood cells (WBC), red blood cells (anemia) and platelets (thrombocytopenia). Patients usually need blood and platelet transfusions to treat anemia and thrombocytopenia until the new graft beings producing blood cells. The duration of bone marrow suppression can be shortened by infusing an optimal number of stem cells and utilizing growth factors that hasten the recovery of blood cell production.
During the 2-3 weeks it takes the new bone marrow to grow and produce white blood cells, patients are susceptible to infection and require the administration of antibiotics to prevent bacterial and fungal infections. Bacterial infections are most common during this initial period of neutropenia. Stem cells collected from peripheral blood tend to engraft faster than bone marrow and may reduce the risk of infection by shortening the period of neutropenia. The use of white blood cell growth factors Neupogen® or Neulasta® ensures that most patients will experience the recovery of their WBC count with 2 weeks of stem cell infusion.
The immune system takes even longer to recover than white blood cell production, with a resultant susceptibility to some bacterial, fungal and viral infections for weeks to months. Patients are often required to take antibiotics to prevent infections from occurring for weeks to months after initial recovery from allogeneic stem cell transplant. Prophylactic antibiotic administration can prevent Pneumocystis carini pneumonia and some bacterial and fungal infections. Prophylactic antibiotics can also decrease the incidence of herpes zoster infection, which commonly occurs after high-dose chemotherapy and allogeneic stem cell transplant.
Mucositis is an inflammation of the lining of the mouth or gastrointestinal (GI) tract. This condition is also commonly referred to as mouth sores. Mucositis is one of the most common side effects of the intensive therapy that precedes stem cell transplantation. The majority of patients treated with a stem cell transplant will develop mucositis. In fact, patients undergoing stem cell transplantation have complained that mucositis is the single most debilitating side effect from treatment.1 Chemotherapy and radiation therapy are effective at killing rapidly dividing cells, a hallmark characteristic of some cancers. Unfortunately, many normal cells in the body are also rapidly dividing and can sustain damage from chemotherapy as well. The entire GI tract, including the mouth and the throat, is made up of cells that divide rapidly. For this reason, the GI tract is particularly susceptible to damage by chemotherapy and radiation treatment, which results in mucositis.
It is important to understand that mucositis is temporary and typically resolves within a few weeks. Improvement begins as engraftment occurs and patients are given medications to help control the pain and associated symptoms to keep them more comfortable.
Sinusoidal Obstructive Syndrome (SOS)-Veno-Occlusive Disease of the Liver (VOD)
High-dose chemotherapy can result in damage to the liver, which can be serious and even fatal. This complication is increased in patients who have substantial amounts of previous chemotherapy and/or radiation therapy, a history of liver damage or hepatitis. Sinusoidal Obstructive Syndrome of the liver typically occurs in the first two weeks after high-dose chemotherapy treatment, often beginning as early as 3-4 days after stem cell infusion. Transplant teams carefully monitor patients for the development of SOS by checking blood bilirubin levels and daily weights and urine output for signs of early fluid retention and liver damage; the hallmark of SOS. Patients that develop SOS typically experience symptoms of abdominal fullness or swelling, liver tenderness and weight gain from fluid retention. A new drug called defibrotide has has shown promise in treating patients with SOS, it is currently available in Europe and in clinical trials in the United States.
Interstitial Pneumonia Syndrome (IPS)
High-dose chemotherapy can cause damage directly to the cells of the lungs. This may be more frequent in patients treated with certain types of chemotherapy and/or radiation therapy given prior to the transplant. This complication of transplant may occur anytime from a few days after high-dose chemotherapy to several months after treatment. Patients typically experience a dry non-productive cough or shortness of breath. Both patients and their doctors often misinterpret these early symptoms. Patients experiencing shortness of breath or a new cough after allogeneic transplant should bring this to the immediate attention of their doctor since this can be a serious and even fatal complication.
Graft failure occurs when bone marrow function does not return. The graft may fail to grow or be rejected in the patient resulting in bone marrow failure with the absence of red blood cell, white blood cell and platelet production. This results in infection, anemia and bleeding. Insufficient immune system suppression is the main cause of graft rejection. Graft failure may also occur in patients with extensive marrow fibrosis before transplantation, a viral illness or from the use of some drugs (such as methotrexate). In leukemia patients, graft failure often is associated with a recurrence of cancer; the leukemic cells may inhibit the growth of the transplanted cells. In some cases, the reasons for graft failure are not known.
Long-Term Side Effects of Allogeneic Stem Cell Transplant
There are several long-term or late side effects that result from the chemotherapy and radiation therapy used with allogeneic stem cell transplant. The frequency and severity of these problems depends on the radiation or chemotherapy that was used to treat the patient. It is important to have the doctors providing your care explain the specific long-term side effects that can occur for the actual treatment they propose. Complications you should be aware of include the following:
Chemo Brain: Chemo brain refers to changes in cognitive function, such as loss of memory and inability to think clearly or perform some daily functions. Researchers have not been able to pinpoint the cause of chemo brain, but current studies are evaluating brain structure and function in order to better understand the effects of chemotherapy on the brain. To better understand more about how chemo brain affects patients several years after treatment, researchers evaluated 92 patients at the Fred Hutchinson Cancer Research Center in Seattle that had been treated for blood cancers with chemotherapy and bone marrow or stem cell transplants. The patients were matched with controls who had not undergone cancer treatment.
- During the five years following treatment, survivors were able to recover much of their cognitive function. Verbal recall (the ability to call up a known word—one that is on the “tip of the tongue”), however, was more difficult to recover than other functions.
- Some functions, such as verbal fluency and executive function (including abilities such as planning and organizing) improved during the five years post-treatment, whereas motor skills did not improve during this time.
- At five years after treatment 41.5% of survivors had deficits that were mild or greater compared with 19.7% of controls.
Though it appears that the cognitive impairment following chemotherapy known as chemo brain is largely temporary and likely to improve during the five years following treatment, difficulties persist for a significant number of survivors (more than 40%). An understanding of the risk factors and reasons for these lasting impairments is needed, as are improved methods to rehabilitate cognitive function.2
Cataracts: Cataracts occur in the overwhelming majority of patients who receive total body irradiation in their treatment regimen. In patients who receive chemotherapy without total body irradiation, cataracts are much less frequent. The onset of cataracts typically begins 18-24 months following treatment. Patients who have received large doses of steroids will have an increased frequency and earlier onset of cataracts. Patients are advised to have slit lamp eye evaluations annually and early correction with artificial lenses.
Infertility: The overwhelming majority of women who receive total body irradiation will be sterile. However, some prepubertal and adolescent females do recover ovulation and menstruation. In patients who receive chemotherapy only preparative regimens, the incidence of sterility is more variable and more age related, i.e., the older the woman is at the time of treatment the more likely chemotherapy will produce anovulation. These are important considerations because of the need for hormone replacement. All females should have frequent gynecologic follow-up. The overwhelming majority of men who receive total body irradiation will become sterile. Sterility is much more variable after chemotherapy only regimens. Men should have sperm counts done to determine whether or not sperm are present and should be examined over time, as recovery can occur.
New cancers: Treatment with chemotherapy and radiation therapy is known to increase the risk of developing a new cancer. These are called “secondary cancers” and may occur as a late complication of high-dose chemotherapy. Patients treated with high-dose chemotherapy and allogeneic stem cell transplantation appear to have an increased risk of developing a secondary cancer. In a report evaluating almost 20,000 patients treated with allogeneic stem cell transplantation, 80 patients developed a new cancer. This represents an approximate 2.5% greater risk compared to normal individuals. Results from this analysis demonstrate that the overall risk of developing second cancers 5 years following treatment with allogeneic stem cell transplant was 1.6%. Ten years following treatment, this risk increased to 6.4%.3
The longer patients survived after high-dose chemotherapy and allogeneic stem cell transplantation, the greater the risk of developing a secondary cancer. Patients treated with total body irradiation appear to be more likely to develop new cancer than those treated with lower radiation doses or high-dose chemotherapy. High-dose chemotherapy and allogeneic stem cell transplant is increasingly used to treat certain cancers because it improves cure rates. Patients should be aware of the risk of secondary cancer and discuss the benefits and risks of high-dose chemotherapy with their physician.
Diabetes and Hypertension
Researchers affiliated with the Bone Marrow Transplant Survivor Study recently conducted a study involving 1,089 survivors who had undergone allogeneic or autologous stem cell transplants. The average follow-up was 8.6 years. The main findings of this study included the following:
- A 3.65-fold increase in diabetes was observed in allogeneic transplant recipients.
- A 2.06-fold increase in hypertension (high blood pressure) was observed in allogeneic transplant recipients.
- Total body irradiation was associated with an increased risk of diabetes.
- Autologous stem cell transplants were not associated with an increased risk of diabetes or hypertension.
These authors suggested that allogeneic transplant recipients may also be at increased risk of future side effects including diabetes and hypertension.6
Stem Cell Processing
A typical stem cell collection is unmodified and contains red blood cells, immune cells and stem cells when it is processed. The stem cell collection however, can be modified with the intent of improving treatment of cancer. With allogeneic stem cell transplantation, T-lymphocytes are an immune cell present in the stem cell collection and are responsible for causing graft-versus-host disease in the patient after infusion of the stem cells.
In the 1980’s, many cancer centers developed techniques for the removal of T-lymphocytes from bone marrow stem cell collections in order to reduce the severity of graft-versus-host disease. This was mainly accomplished by mixing the stem cells with monoclonal antibodies that recognized T-lymphocytes. This process was referred to as T-cell depletion and the removal of T-lymphocytes did decrease the incidence of graft-versus-host disease in patients undergoing allogeneic stem cell transplant. Unfortunately, removal of T-lymphocytes also caused an increased risk of graft failure and doctors learned that some T-lymphocytes are necessary for bone marrow engraftment.
Techniques for removal of specific T-lymphocytes from stem cell collections are now available. This process is very appealing because specific groups of T-lymphocytes can be removed or even added back based on the number of cells necessary to achieve the desired effect in the patient. For example, the cells responsible for graft-versus-host disease could be removed and those necessary for engraftment could be infused into the patient.
Scientists have also discovered that stem cells have certain markers (antigens) on their surface that distinguish them from other cells. One of the main antigens on stem cells is the CD34 antigen and positive selection is one technique that has been developed for the separation of stem cells from other cells. CD34 selection uses a device that binds the CD34 positive stem cells and removes them from the other cells in the stem cell collection. CD34 positive selection devices are capable of removing large numbers of non-specific T-lymphocytes from the stem cell product. Unfortunately, they also remove 25%-50% of the stem cells, immune cells and other cells. Many cancer centers are using CD34 positive selection devices and other techniques of stem cell processing in an attempt to change the cell content of stem cell collections in order to improve the safety and potential benefit of allogeneic stem cell transplant.
Cellular Therapy and Enhancement of Immunity after Stem Cell Transplant
Allogeneic stem cell transplants are more effective in preventing cancer recurrences than autologous transplants because the donor cells recognize the cancer as foreign and kill cancer cells immunologically. Despite this graft-versus-leukemia reaction, many patients still experience a cancer recurrence. Several different approaches that attempt to enhance this graft-versus-leukemia effect are currently being evaluated.
Donor White Blood Cell Infusions: In patients who do not have graft-versus-host disease, infusions of white blood cells from the donor are being evaluated to prevent or treat cancer recurrences that occur after allogeneic stem cell transplant. In some studies, donor white cells are combined with a biologic response modifier such as interleukin-2 to further enhance the graft-versus-leukemia reaction.
Lymphocytes are white blood cells that are part of the body’s immune system and are capable of destroying cancer cells. Doctors have been trying for several years to use lymphocytes reactive specifically against cancer cells as a form of treatment. For many reasons, this has been a difficult goal to achieve. First, billions of lymphocytes are needed in order to have a therapeutic effect because it takes several lymphocytes to kill a single cancer cell. Thus, in order for lymphocyte infusions to be practical therapy, extremely large numbers of specific immune lymphocytes need to be produced. Getting lymphocytes to grow and multiply in culture systems outside the body has been difficult. Second, the lymphocytes grown in culture have to be specifically reactive to the cancer cell that has to be killed. Lymphocytes normally attack and kill a variety of foreign invaders, but each lymphocyte is specific and only kills one target and no other. Third, the immune lymphocytes must survive and not be destroyed when infused into a patient with cancer.
White blood cells can be collected in large numbers from the original, healthy donor of stem cells by apheresis and then infused back into the relapsed patient. This procedure, known as Donor Leukocyte Infusion, or DLI has resulted in 70% to 75% complete remission rates in chronic leukemia patients. Unfortunately, the standard DLI procedure is associated with very high rates of severe and potentially fatal GvHD.
Unfortunately, the use of donor lymphocytes can also be associated with the development of graft-versus-host disease. The risk for developing graft-versus-host disease may be decreased if a specific type of lymphocyte, the CD8 lymphocyte, is removed. Until recently, there has not been an effective and efficient way to remove, or deplete, these CD8 cells from the other donor lymphocytes.
Ex Vivo Expansion
During an allogeneic bone marrow or blood stem cell transplant, it is necessary to harvest or collect a relatively small number of “stem cells” to repopulate the bone marrow after it has been destroyed by radiation therapy and/or high-dose chemotherapy. In some instances, it is difficult to collect enough stem cells to provide rapid and safe recovery of bone marrow function. In the past, bone marrow was obtained by several hundred needle punctures from the hip bones under general anesthesia. More recently, stem cells have been obtained from the peripheral blood through a procedure called apheresis. Collection of blood stem cells requires one or more apheresis procedures to obtain enough stem cells for a transplant, but is relatively safe and does not require general anesthesia. However, apheresis requires access to two large veins, which is not always possible, especially in small patients, without the placement of special catheters. Some stem cell donors, especially umbilical cord blood, contain insufficient stem cells for optimal recovery without stem cell transplant.
The procedure for growing stem cells outside the body is called ex-vivo expansion. Over the years, doctors have discovered the hormones that tell stem cells to divide and multiply. They can now add these hormones to a sterile culture system outside the body. Thus, one could place small numbers of stem cells in a culture system with the appropriate hormones and produce a lot of “stem cells” suitable for transplantation. The results of clinical trials now suggest that small quantities of stem cells collected from umbilical cord blood can be ex-vivo expanded and facilitate stem cell transplantation.
- Bellm LA, Epstein JB, Rose-Ped A, et al. Patient Reports of Complications of Bone Marrow Transplantation. Support Care Cancer. 2000;8:33-39.
- Syrjala KL, Artherholt SB, Kurland BF, et al. Prospective neurocognitive function over 5 years after allogeneic hematopoietic cell transplantation for cancer survivors compared with matched controls at 5 years. The Journal of Clinical Oncology [early online publication]. May 2, 2011.
- Journal of Clinical Oncology, Vol 19, No2, pp 464-471, 2001)
- Survival, Nonrelapse Mortality, and Relapse-Related Mortality After Allogeneic Hematopoietic Cell Transplantation: Comparing 2003–2007 Versus 2013–2017 Cohorts
- Ciurea SO, Zhang MJ, Bacigalupo AA, et al. Haploidentical transplant with post-transplant cyclophosphamide versus matched unrelated donor transplant for acute myeloid leukemia. Blood [early online publication]. June 30, 2015.
- Baker KS, Ness KK, Steinberger J, et al. Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study. Blood. 2007;109:1765-1772.